Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease.
BACKGROUND
Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction.


OBJECTIVE
The current study was designed to determine the role of Nrf2-mediated cytoprotective mechanisms in murine airway RSV disease.


METHODS
Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf2(+/+) and Nrf2(-/-) mice were treated orally with sulforaphane (an Nrf2-ARE inducer) or phosphate-buffered saline before RSV infection.


RESULTS
RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. Compared with Nrf2(+/+) mice, significantly attenuated viral clearance and IFN-gamma, body weight loss, heightened protein/lipid oxidation, and AP-1/NF-kappaB activity along with suppressed antioxidant induction was found in Nrf2(-/-) mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf2(+/+) but not in Nrf2(-/-) mice.


CONCLUSIONS
The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf2-ARE pathway in host defense against RSV.
Cho
Hye-Youn
HY
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, 27709, USA. cho2@niehs.nih.gov
Imani
Farhad
F
Miller-DeGraff
Laura
L
Walters
Dianne
D
Melendi
Guillermina A
GA
Yamamoto
Masayuki
M
Polack
Fernando P
FP
Kleeberger
Steven R
SR
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid; D002021:Buffers; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D017879:Isothiocyanates; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010710:Phosphates / Q000008:administration & dosage; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000378:metabolism*; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage
D016588:Anticarcinogenic Agents; D002021:Buffers; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D010710:Phosphates; D013454:Sulfoxides; D013861:Thiocyanates; D012965:Sodium Chloride; C016766:sulforaphane